Chronic pathological pain remains an area of significant unmet medical need. Current treatments, such as duloxetine, are efficacious only in a limited subset of patients and are associated with dose-limiting side effects, such as nausea and somnolence. Advanced Glycation End products (AGEs) and one of their receptors (RAGE) have been implicated in the ethiology of chronic pain syndromes, including those of diabetic neuropathy and fibromyalgia.
The Receptor for Advanced Glycation Endproducts (RAGE) is a multi-ligand receptor of the immunoglobulin superfamily. Extracellular domain of RAGE includes one N-terminal V-type and two C2-type immunoglobulin domains usually termed C1 and C2. Ligands of RAGE include AGEs (the products of nonenzymatic glycation and oxidation of proteins and lipids such as carboxymethyl lysine (CML) adducts), Aβ, S100/calgranulins and amphoterin. Different ligands have been shown to bind to different domains within RAGE. For example, S100b, HMGB1 and amyloid Aβ are reported to bind to the V-domain, as evidenced by various groups (Ostendorp et al. EMBO J. 2007; 26(16): 3868-3878; Leclerc E et al, J Biol. Chem. 2007; 282 (43): 31317-31331; WO 2007/109749 (A2). Ligands of C1 (first C2-like) domain and C2 (second C2-like) domain were reported to include S100A12 (also called ENRAGE or Calgranulin C) and Aβ in case of C1 (Hofmann M A et al. Cell, 1999; 97: 889-901), and S100A6 (Leclerc E et al, J Biol. Chem. 2007; 282 (43): 31317-31331). In some cases, the precise location of binding of a ligand to RAGE remains unclear.